Ocular diseases and disorders, including dysfunctions of the eye, eyelids, eyelashes, or lacrimal (tear) system and neuro-opthalmic diseases, affect over three million people per year in the United States alone (Monnet, et al., Ophthalmology, 111(4):802-9 (2004)). Many of these cases are difficult to diagnose, and even more difficult to treat. Because the eye in general (especially the cornea) is not vascularized, systemic drugs do not readily permeate it and are generally not used for therapy of ocular diseases or disorders. To date, the topical application of antibiotics has been the preferred treatment, however, the results have been limited results. Consequently, a wide variety of new, alternative compounds have been proposed for use in the treatment of ocular disorders and diseases.
One compound currently used for the treatment of ocular diseases, especially dry eye disease, is the immunomodulator Cyclosporin A. Cyclosporin A (CsA), a fungal-derived immunosuppressive agent, has shown initial promise for the treatment of dry eye/chronic dry eye disease (CDED) (in dogs), severe uveitis, vernal conjunctivitis and to prevent corneal graft rejection in humans; see, for example, Nussenblatt et al., Survey of Ophthalmology, 31 (November-December 1986); and BenEzra et al., American Journal of Ophthalmology, 101: p. 298 (1986). Most recently, cyclosporin A (RESTASIS™, cyclosporin ophthalmic emulsion, 0.05%) has received FDA approval for use in increasing the tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca (chronic dry eye).
While cyclosporin A (CsA) has been shown to be effective initially, formulations containing this compound reported significant side effects, including ocular burning, kidney damage and predilection for tumor formation. This suggests that long term therapeutic use, which is usually necessary in the case of ocular diseases and disorders, may present a risk. In addition, due to its size and structure, CsA is not water soluble (Merck Index, 13th Ed, no. 2781) and currently must be delivered in a lipophilic formulation which is not optimal for topical ophthalmic use. Further, it often requires several weeks of RESTASIS™ treatment (one drop twice a day) to produce a clinical therapeutic effect and it may take up to 6 months for maximum improvement. Consequently, RESTASIS™ may only sometimes be considered to be an appropriate drug for immediate relief of an uncomfortable irritated eye, or other ocular conditions.
Among the available treatment options for immediate relief of optical disorders such as dry eye disease, topical corticosteroids (e.g., LOTEMAX (Loteprednol Etabonate; Bausch & Lomb), FML or VEXOL  1% (rimexolone ophthalmic suspension; Alcon, Inc.) have the most rapid onset of action. They may be used for the short-term (2 to 4 weeks). However, the use of steroids in the treatment of ocular diseases and disorders is not without problems, as long-term use of steroid eyedrops can cause a rise in eye pressure (perhaps even glaucoma) and development of a cataract. Therefore, compounds which are devoid of these steroid-related side effects are being sought for use as long-term anti-inflammatory agents.
One such agent is BIOTEARS (Biosyntryx), a twice-daily oral nutraceutical formulation available in very small gel caps and designed to enhance the body's ability to absorb and convert Omega 6 fatty acids to a tear-specific series E1 prostaglandins, which have anti-inflammatory properties that alleviate the signs and symptoms of dry eyes. BIOTEARS also contains the iron binding protein lactoferrin, which reportedly helps to inhibit mild viral and bacterial eye infections that cause discomfort for a large number of contact lens wearers.
U.S. Pat. No. 6,565,861 describes formulations for application to mammalian eyes which contain a lipid binding protein (a tear-specific prealbumin, such as lysozyme, lactoferrin, 1 gA, and β-lactoglobulin) and a polar lipid (such as phospholipids and glycolipids), present as a soluble complex in an aqueous electrolyte. The formulations described have shear-thinning and surface tension properties to natural tears and are therefore reportedly useful as artificial tear substitutes for the treatment of dry eyes (e.g. keratoconjunctivitis sicca) as well as in ophthalmic applications in general.
The immunomodulating drug tacrolimus (PROGRAF, previously known as FK-506; Fujisawa USA), often used as a medication for the prophylaxis of rejection in liver transplants and recently approved by the FDA for use as an immunosuppressive for the prevention of organ rejection in kidney transplant recipients, has been reported to have utility as an immunomodulating drug when applied topically in the treatment of a variety of dermatoses. U.S. Pat. No. 6,489,335 (issued Dec. 3, 2002) suggests the non-systemic use of tacrolimus in the treatment of ocular diseases, including dry eye disease, uveitis, scleritis, neuritis, and papilits. However, the reported side effects associated with the use of this compound--including tremors, hypertension, hypophosphatemia, creatinine increase, headache, and diarrhea--suggest that the use of this compound is less than optimal for the treatment of ocular disorders.
U.S. Pat. No. 6,569,903 describes an adrenergic β-receptor agonist having a high selectivity toward an adrenergic β2 receptor, usable as preventives or therapeutics for xerophthalmic disorders and keratoconjunctival disorders. The adrenergic b-receptor agonists described that are reportedly suitable for use include clenbuterol, fenoterol, salbutamol, salmeterol, hexoprenaline, pirbuterol, mabuterol, bambuterol, formoterol, meluadrine, tulobuterol, levosalbutamol, as well as salts of these compounds.
Steroids and antimetabolite compounds, such as cyclophosphamide, have been used orally to treat severe uveitis, such as that associated with Behcet's disease. Oral steroid therapy is usually accompanied by the topical use of steroid therapy (ocular) to more rapidly control the inflammation. Steroids are also typically used in conjunction with antiviral, antiparasitic or antifungal agents to treat uveitis associated with microbial infections. Both antimetabolite and steroid therapies are general immunosuppressive treatments with both ocular and systemic side effects. Development of central serous chorioretinopathy (CSC) following the administration of corticosteroids by diverse routes is a well-known fact (Bowie, E. M., et al., Arch. Ophthalmo., 122 (2): pp. 281-283 (2004); De Nus, E., et al., Bul. Soc. Belge Ophtalmol., 289: pp. 35-41 (2003)). Further, acute visual loss after the use of systemic corticosteroids in patients with long-standing ocular inflammatory disorders in whom CSC could initially be misinterpreted as a worsening of the primary inflammatory condition has recently been reported (Schalenbourg A, Leys A, De Courten C, Coutteel C, Herbort C P., “Corticosteroid-induced central serous chorioretinopathy in patients with ocular inflammatory disorders”, Klinische Monatsblätter für Augenheilkunde, 219(4): pp. 264-7 (2002)), further supporting the search for compounds useful in the treatment of ocular diseases and disorders while simultaneously minimizing the ocular and/or systemic side effects associated with the treatment.
Lysostaphin, a protein of approximately 27,000 Daltons, is a bacterial endopeptidase highly lethal to S. aureus and S. epidermidis that has recently been reported by O'Callaghan (U.S. Pat. No. 6,315,996) to be an effective antibiotic for topical treatment of Staphylococcus corneal infections (keratitis). According to the patent, treatment by lysostaphin was more potent than any of the smaller antibiotics that have been previously tested (e.g., tetracyclines, erythromycins, cephalosporins, vancomycin, aminoglycosides, or fluoroquinolones) for use against keratitis. Moreover, topical application of lysostaphin was shown to be effective against some of the highly antibiotic-resistant Staphylococcus strains.
Other approaches to the treatment of ocular disorders, especially dry eye disease, include the administration of nicotinic acetylcholine receptor agonists (see, for example, U.S. Pat. No. 6,277,855; PCT Publication No. WO 0180844A3), the administration of antimicrobial peptides derived from α-melanocyte-stimulating hormone and its equivalents (see, for example, U.S. patent application No. 2004 0033955), and using uridine triphosphates and related compounds as potential therapeutic treatments (see, for example, U.S. Pat. No. 5,900,407; European Patent Application No. 1003474). Uridine triphosphate and compositions containing this and related dinucleotides have also been described for use in reducing intraocular pressure (see, for example, European Patent Application No. 130 7191 A2), treating retinal degeneration (see, for example, EP 1280536), treating otis media (see, for example, U.S. Pat. No. 6,423,694), affecting cornea epithelium extension (see, for example, Japanese Patent Application No. 2002053492A2), and stimulating the removal of fluid in retinal detachment and retinal edema (see, for example, U.S. Pat. No. 6,596,725).
Based upon the limited success of other chemotherapeutic approaches to ocular diseases to date, there exists a need to develop therapeutics for the treatment of ocular diseases and disorders.
It is an object of the present invention to provide improved methods for the treatment of a variety of ocular diseases and disorders.
It is another object of the present invention to provide compositions and formulations for the treatment of ocular diseases and disorders.